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A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer.

TitleA Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer.
Publication TypeJournal Article
Year of Publication2017
AuthorsMayer IA, Abramson VG, Formisano L, Balko JM, Estrada MV, Sanders ME, Juric D, Solit D, Berger MF, Won HH, Li Y, Cantley LC, Winer E, Arteaga CL
JournalClin Cancer Res
Volume23
Issue1
Pagination26-34
Date Published2017 Jan 01
ISSN1078-0432
Abstract

PURPOSE: Alpelisib, a selective oral inhibitor of the class I PI3K catalytic subunit p110α, has shown synergistic antitumor activity with endocrine therapy against ER(+)/PIK3CA-mutated breast cancer cells. This phase Ib study evaluated alpelisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER(+) breast cancer refractory to endocrine therapy.

EXPERIMENTAL DESIGN: Twenty-six patients received letrozole and alpelisib daily. Outcomes were assessed by standard solid-tumor phase I methods. Tumor blocks were collected for DNA extraction and next-generation sequencing.

RESULTS: Alpelisib's maximum-tolerated dose (MTD) in combination with letrozole was 300 mg/d. Common drug-related adverse events included hyperglycemia, nausea, fatigue, diarrhea, and rash with dose-limiting toxicity occurring at 350 mg/d of alpelisib. The clinical benefit rate (lack of progression ≥6 months) was 35% (44% in patients with PIK3CA-mutated and 20% in PIK3CA wild-type tumors; 95% CI, 17%-56%), including five objective responses. Of eight patients remaining on treatment ≥12 months, six had tumors with a PIK3CA mutation. Among evaluable tumors, those with FGFR1/2 amplification and KRAS and TP53 mutations did not derive clinical benefit. Overexpression of FGFR1 in ER(+)/PIK3CA mutant breast cancer cells attenuated the response to alpelisib in vitro CONCLUSIONS: The combination of letrozole and alpelisib was safe, with reversible toxicities. Clinical activity was observed independently of PIK3CA mutation status, although clinical benefit was seen in a higher proportion of patients with PIK3CA-mutated tumors. Phase II and III trials of alpelisib and endocrine therapy in patients with ER(+) breast cancer are ongoing. Clin Cancer Res; 23(1); 26-34. ©2016 AACR.

DOI10.1158/1078-0432.CCR-16-0134
Alternate JournalClin. Cancer Res.
PubMed ID27126994
PubMed Central IDPMC5085926
Grant ListP30 CA016672 / CA / NCI NIH HHS / United States
P50 CA098131 / CA / NCI NIH HHS / United States
R01 GM041890 / GM / NIGMS NIH HHS / United States
P30 CA068485 / CA / NCI NIH HHS / United States
K23 CA127469 / CA / NCI NIH HHS / United States

Weill Cornell Medicine
Cantley Lab
Weill Cornell Medical College Meyer Cancer Center
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